Nonrandom utilization of codon pairs in Escherichia coli.

Gutman, G A; Hatfield, G W

doi:10.1073/pnas.86.10.3699

Cited by 263RNA and protein synthesis mechanismsBacterial Genetics and BiotechnologyGenomics and Phylogenetic Studies

Nonrandom utilization of codon pairs in Escherichia coli.

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Gutman, G A, Hatfield, G W·1989·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.86.10.3699PMC PMC287207

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Abstract

We have analyzed protein-coding sequences of Escherichia coli and find that codon-pair utilization is highly biased, reflecting overrepresentation or underrepresentation of many pairs compared with their random expectations. This effect is over and above that contributed by nonrandomness in the use of amino acid pairs, which itself is highly evident; it is much weaker when nonadjacent codon pairs are examined and virtually disappears when pairs separated by two or three intervening codons are evaluated. There appears to be a high degree of directionality in this bias: any codon that participates in many nonrandom pairs tends to make both over- and underrepresented pairs, but preferentially as a left- or right-hand member. We show a relationship between codon-pair utilization patterns and levels of gene expression: genes encoding proteins expressed at high levels tend to contain more abundant, but more highly underrepresented, codon pairs, relative to genes expressed at low levels. The nonrandom utilization of codon pairs may be a consequence of their effects on translational efficiency, which in turn may be related to the compatibility of adjacent aminoacyl-tRNA isoacceptors at the A and P sites of a translating ribosome.

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Components of Vectors for Gene Transfer and Expression in Mammalian Cells
Makrides, S. C. (1999) · Protein Expression and Purification · doi:10.1006/prep.1999.1137 · Cited by 87 · see citing works
Mechanism of Virus Attenuation by Codon Pair Deoptimization
Groenke, N., Trimpert, J., Merz, S., Conradie, A. M., Wyler, E., Zhang, H., Hazapis, O.-G., Rausch, S., Landthaler, M., Osterrieder, N., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107586 · Cited by 85 · see citing works
“This is an open access article under the CC BY-N be expected based on the overall frequencies of two codons that form a particular codon pair (Coleman et al., 2008; Gutman and Hatfield, 1989; Mueller et al., 2006).”
Background
Changes in codon-pair bias of human immunodeficiency virus type 1 have profound effects on virus replication in cell culture
Martrus, G., Nevot, M., Andres, C., Clotet, B., & Martinez, M. A. (2013) · Retrovirology · doi:10.1186/1742-4690-10-78 · Cited by 85 · see citing works
“Although the reasons are still not well understood, some codon pairs occur more frequently, and others less frequently, than expected [12].”
Background
Functionally acceptable substitutions in two α‐helical regions of λ repressor
Reidhaar-Olson, J. F., & Sauer, R. T. (1990) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.340070403 · Cited by 84 · see citing works
Synonymous Virus Genome Recoding as a Tool to Impact Viral Fitness
Martı́nez, M. Á., Jordan-Paiz, A., Franco, S., & Nevot, M. (2015) · Trends in Microbiology · doi:10.1016/j.tim.2015.11.002 · Cited by 81 · see citing works
“coli suggested that the frequency with which codons are juxtaposed is nonrandom [50].”
Background
Codon pairs in the genome of Escherichia coli
Boycheva, S., Chkodrov, G., & Ivanov, I. G. (2003) · Bioinformatics · doi:10.1093/bioinformatics/btg082 · Cited by 81 · see citing works
“In an early study based on the analysis of 237 E.coli protein coding genes (Gutman and Hatfield, 1989) showed that some codon pairs were overrepresented and others were underrepresented in comparison with the theoretically predicted means.”
BackgroundInfluential
Ribosome dynamics and mRNA turnover, a complex relationship under constant cellular scrutiny
Morris, C., Cluet, D., & Ricci, E. (2021) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1658 · Cited by 71 · see citing works
“In some bacteria, lower eukaryotes (such as S. cerevisiae, C. elegans, and D. melanogaster) and plants (A. thaliana), codon usage has been shown to be biased towards the most abundant tRNAs (Duret & Mouchiroud, 1999; Grantham et al., 1980; Gutman & Hatfield, 1989; Ikemura, 1985).”
Background
Synthetic gene design—The rationale for codon optimization and implications for molecular pharming in plants
Webster, G. R., Teh, A. Y., & K‐C., J. (2016) · Biotechnology and Bioengineering · doi:10.1002/bit.26183 · Cited by 80 · see citing works
Codon-Resolution Analysis Reveals a Direct and Context-Dependent Impact of Individual Synonymous Mutations on mRNA Level
Chen, S., Li, K., Cao, W., Wang, J., Zhao, T., Huan, Q., Yang, Y., Wu, S., & Qian, W. (2017) · Molecular Biology and Evolution · doi:10.1093/molbev/msx229 · Cited by 76 · see citing works
“The variable impact of an individual synonymous mutation is unlikely caused by the interaction between neighboring codons or tRNA recycling It has been proposed that two mechanisms, the interaction between neighboring codons and the reuse of synonymous codons recognized by the same tRNA (tRNA recycling), can regulate…”
Background
Zika Virus Attenuation by Codon Pair Deoptimization Induces Sterilizing Immunity in Mouse Models
Li, P., Ke, X., Wang, T., Tan, Z., Luo, D., Miao, Y., Sun, J., Zhang, Y., Liu, Y., Hu, Q., et al. (2018) · Journal of Virology · doi:10.1128/jvi.00701-18 · Cited by 74 · see citing works
“88 Codon pair bias is interpreted as the unequal frequency in the usage of synonymous 89 codon pairs in certain species (27-29).”
Background
The translational termination signal database
Brown, C. M., Dalphin, M. E., Stockwell, P. A., et al. (1993) · Nucleic Acids Research · doi:10.1093/nar/21.13.3119 · Cited by 74 · see citing works
Optimizing scaleup yield for protein production: Computationally Optimized DNA Assembly (CODA) and Translation Engineering™
Hatfield, G. W., & Roth, D. A. (2007) · Biotechnology annual review · doi:10.1016/s1387-2656(07)13002-7 · Cited by 70 · see citing works
Self-citation
Codon usage biases co-evolve with transcription termination machinery to suppress premature cleavage and polyadenylation
Zhou, Z., Dang, Y., Zhou, M., Yuan, H., & Liu, Y. (2018) · eLife · doi:10.7554/elife.33569 · Cited by 69 · see citing works
Computer-aided codon-pairs deoptimization of the major envelope GP5 gene attenuates porcine reproductive and respiratory syndrome virus
Ni, Y.-Y., Zhao, Z., Opriessnig, T., Subramaniam, S., Zhou, L., Cao, D., Cao, Q. M., Yang, H., & Meng, X. (2014) · Virology · doi:10.1016/j.virol.2013.12.009 · Cited by 68 · see citing works
“It is known that, among the synonymous codon pairs encoding the same amino acid residues, some codon pairs occur more frequently than others in certain species (Fedorov et al., 2002; Gutman and Hatfield, 1989; Moura et al., 2007), which is known as codon-pair bias.”
Background
The effect of context on synonymous codon usage in genes with low codon usage bias
Bulmer, M. G. (1990) · Nucleic Acids Research · doi:10.1093/nar/18.10.2869 · Cited by 66 · see citing works
Comparison of characteristics and function of translation termination signals between and within prokaryotic and eukaryotic organisms
Cridge, A. G. (2006) · Nucleic Acids Research · doi:10.1093/nar/gkl074 · Cited by 62 · see citing works
Mutations to nonsense codons in human genetic disease: implications for gene therapy by nonsense suppressor tRNAs
Atkinson, J., & Martin, R. H. (1994) · Nucleic Acids Research · doi:10.1093/nar/22.8.1327 · Cited by 61 · see citing works
Recoding of the Vesicular Stomatitis Virus L Gene by Computer-Aided Design Provides a Live, Attenuated Vaccine Candidate
Wang, B., Chen, Y., Tekes, G., Mueller, S., Paul, A. V., Whelan, S. P. J., & Wimmer, E. (2015) · mBio · doi:10.1128/mbio.00237-15 · Cited by 59 · see citing works
“Here, we report attempts to develop a live attenuated VSV strain, making use of a genetic phenomenon known as codon pair bias (CPB) (15, 16).”
Method
Physical and genetic map of the Neisseria gonorrhoeae strain MS11‐N198 chromosome
Bihlmater, A., Römling, U., Meyer, T. F., et al. (1991) · Molecular Microbiology · doi:10.1111/j.1365-2958.1991.tb02099.x · Cited by 58 · see citing works
The Ongoing Quest to Crack the Genetic Code for Protein Production
Nieuwkoop, T., Finger‐Bou, M., John van der, O. O. S. T., & Claassens, N. J. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.09.014 · Cited by 55 · see citing works
Impact of C‐terminal amino acid composition on protein expression in bacteria
Weber, M. L., Burgos, R., Yus, E., Yang, J., Lluch‐Senar, M., & Serrano, L. G. (2020) · Molecular Systems Biology · doi:10.15252/msb.20199208 · Cited by 54 · see citing works
Combined protein construct and synthetic gene engineering for heterologous protein expression and crystallization using Gene Composer
Raymond, A. C., Lovell, S., Lorimer, D. D., Walchli, J., Mixon, M. B., Wallace, E., Thompkins, K. B., Archer, K., Burgin, A. B., & Stewart, L. J. (2009) · BMC Biotechnology · doi:10.1186/1472-6750-9-37 · Cited by 55 · see citing works
“coli [21-23].”
Bicodon bias can determine the role of synonymous SNPs in human diseases
McCarthy, C. B., Carrea, A., & Diambra, L. A. (2017) · BMC Genomics · doi:10.1186/s12864-017-3609-6 · Cited by 54 · see citing works
“In addition, we have also computed the residual score χ2, defined in [42], which indicates when the observed bicodon bias can be explained, or not, by the codon usage bias.”
Criteria for confirming sequence periodicity identified by Fourier transform analysis: Application to GCR2, a candidate plant GPCR?
Illingworth, C. J. R., Parkes, K. E. B., Snell, C. R., et al. (2007) · Biophysical Chemistry · doi:10.1016/j.bpc.2007.11.004 · Cited by 54 · see citing works
Nonuniform size distribution of nascent globin peptides, evidence for pause localization sites, and a cotranslational protein-folding model
Krasheninnikov, I. A., Komar, A. A., & Adzhubei, I. A. (1991) · Journal of Protein Chemistry · doi:10.1007/bf01025472 · Cited by 47 · see citing works
Codon context and protein synthesis: Enhancements of the genetic code
Buckingham, R. H. (1994) · Biochimie · doi:10.1016/0300-9084(94)90108-2 · Cited by 44 · see citing works
RNA stem-loop enhanced expression of previously non-expressible genes
Paulus, M. (2004) · Nucleic Acids Research · doi:10.1093/nar/gnh076 · Cited by 43 · see citing works
Designed Reduction of Streptococcus pneumoniae Pathogenicity via Synthetic Changes in Virulence Factor Codon-pair Bias
Coleman, J. R., Papamichail, D., Yano, M., et al. (2011) · The Journal of Infectious Diseases · doi:10.1093/infdis/jir010 · Cited by 43 · see citing works
“CPB is observed across the kingdoms of life, can be quantified statistically [1, 2], and”
Background
Intra-genome variability in the dinucleotide composition of SARS-CoV-2
Digard, P., Lee, H. M., Sharp, C., Grey, F. E., & Gaunt, E. R. (2020) · Virus Evolution · doi:10.1093/ve/veaa057 · Cited by 41 · see citing works
“CPB (Gutman and Hatfield, 1989) scores across the SARS-CoV-2 ORFeome were calculated using the SSE v1.”
Method
Genetic Engineering of Polymeric Materials
Tirrell, D. A., Fournier, M. J., & Mason, T. L. (1991) · MRS Bulletin · doi:10.1557/s0883769400056505 · Cited by 41 · see citing works
Live attenuated virus vaccine protects against SARS-CoV-2 variants of concern B.1.1.7 (Alpha) and B.1.351 (Beta)
Trimpert, J., Adler, J. M., Eschke, K., Abdelgawad, A., Firsching, T. C., Ebert, N., Thao, T. T. N., Gruber, A. D., Thiel, V., Osterrieder, N., et al. (2021) · Science Advances · doi:10.1126/sciadv.abk0172 · Cited by 41 · see citing works
“CPD is based on the observation that some codon pairs occur in protein-coding sequences significantly less or more frequently than would be statistically expected (26).”
Background
Limitations of codon adaptation index and other coding DNA‐based features for prediction of protein expression in Saccharomyces cerevisiae
Friberg, M. T., von Rohr, P., & Gonnet, G. H. (2004) · Yeast · doi:10.1002/yea.1150 · Cited by 40 · see citing works
HP-PRRSV is attenuated by de-optimization of codon pair bias in its RNA-dependent RNA polymerase nsp9 gene
Gao, L., Wang, L., Huang, C., Yang, L., Guo, X.-K., Yu, Z., Liu, Y., Yang, P., & Feng, W.-H. (2015) · Virology · doi:10.1016/j.virol.2015.07.012 · Cited by 40 · see citing works
“This phenomenon is termed as codon pair bias (CPB) (Gutman and Hatfield, 1989).”
Background
Human body temperature and new approaches to constructing temperature-sensitive bacterial vaccines
White, M. D., Bosio, C. M., Duplantis, B. N., & Nano, F. E. (2011) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-011-0734-2 · Cited by 39 · see citing works
“Also, changes in the nucleotide sequence could affect the efficiency of translation if rare codons [75, 76] or rare codon pairs [77] for the host organism are introduced.”
Species-Specific Codon Context Rules Unveil Non-Neutrality Effects of Synonymous Mutations
Moura, G., Pinheiro, M. M., Freitas, A. V., Oliveira, J. L., Frommlet, J. C., Carreto, L. C., Soares, A. R., Bezerra, A. R., & Santos, M. A. S. (2011) · PLoS ONE · doi:10.1371/journal.pone.0026817 · Cited by 39 · see citing works
“independent of codon-usage biases [3,4], indicating that these two”
Background
Potential impact of synthetic biology on the development of microbial systems for the production of renewable fuels and chemicals
Picataggio, S. K. (2009) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2009.04.003 · Cited by 39 · see citing works
Codon usage and codon context bias in Xanthophyllomyces dendrorhous
Baeza, M., Alcaı́no, J., Barahona, S., Sepúlveda, D., & Cifuentes, V. (2015) · BMC Genomics · doi:10.1186/s12864-015-1493-5 · Cited by 39 · see citing works
“Codon context bias is likely associated with the accuracy of decoding, indicating the ability of the translational machinery to detect codon pairs present at ribosomal decoding sites [30-33].”
Background
Mechanisms governing codon usage bias and the implications for protein expression in the chloroplast of Chlamydomonas reinhardtii
Fages‐Lartaud, M., Hundvin, K., & Hohmann‐Marriott, M. F. (2022) · The Plant Journal · doi:10.1111/tpj.15970 · Cited by 39 · see citing works
“The expected codon pair frequency ( e ij ) was corrected for the dipeptide bias as previously described (Buchan et al., 2006; Gutman & Hatﬁeld, 1989).”
Influential
In silico methods for predicting functional synonymous variants
Lin, B. C., Katneni, U., Jankowska, K. I., Meyer, D., & Kimchi‐Sarfaty, C. (2023) · Genome biology · doi:10.1186/s13059-023-02966-1 · Cited by 40 · see citing works
Synonymous Codon Ordering: A Subtle but Prevalent Strategy of Bacteria to Improve Translational Efficiency
Shao, Z., Zhang, Y., Feng, X.-Y., Wang, B., & Chen, J. (2012) · PLoS ONE · doi:10.1371/journal.pone.0033547 · Cited by 38 · see citing works
“It has been found that adjacent codon pairs, which encode either the same or different amino acids, have biased occurrence frequencies within a genome [24,25].”
Background
Differential bicodon usage in lowly and highly abundant proteins
Diambra, L. A. (2017) · PeerJ · doi:10.7717/peerj.3081 · Cited by 38 · see citing works
“has been previously established in (Gutman and Hatfield, 1989; Buchan et al., 2006).”
BackgroundMethodResultInfluential
Codon context
Buckingham, R. H. (1990) · Cellular and Molecular Life Sciences · doi:10.1007/bf01936922 · Cited by 38 · see citing works
TISIGNER.com: web services for improving recombinant protein production
Bhandari, B. K., Lim, C. S., & Gardner, P. P. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab175 · Cited by 37 · see citing works
Attenuation of Human Respiratory Viruses by Synonymous Genome Recoding
Nouën, C. L., Collins, P. L., & Buchholz, U. J. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01250 · Cited by 36 · see citing works
“These Leu and Ser mutations did not aﬀect the CB, CPB, CpG content or dinucleotide frequency ( Figure 1D ) (15).”
BackgroundMethodInfluential
Understanding the Genetic Code
Saier, M. H. (2019) · Journal of Bacteriology · doi:10.1128/jb.00091-19 · Cited by 36 · see citing works
Can simple codon pair usage predict protein–protein interaction?
Zhou, Y., Zhou, Y., He, F., Song, J., & Zhang, Z. (2012) · Molecular BioSystems · doi:10.1039/c2mb05427b · Cited by 36 · see citing works
Codon engineering for improved antibody expression in mammalian cells
Carton, J. M., Sauerwald, T. M., Hawley‐Nelson, P., Morse, B. A., Peffer, N. J., Beck, H., Lu, J., Cotty, A., Amegadzie, B. Y., & Sweet, R. (2007) · Protein Expression and Purification · doi:10.1016/j.pep.2007.05.017 · Cited by 34 · see citing works
Spatial Patterns of Gene Expression in Bacterial Genomes
Lato, D. F., & Golding, G. B. (2020) · Journal of Molecular Evolution · doi:10.1007/s00239-020-09951-3 · Cited by 33 · see citing works

Codon contexts in enterobacterial and coliphage genes.
Gouy, M. (1987) · Molecular Biology and Evolution · doi:10.1093/oxfordjournals.molbev.a040450 · Cited by 63 · see citing works
Reduced synonymous substitution rate at the start of enterobacterial genes
Eyre‐Walker, A., & Bulmer, M. G. (1993) · Nucleic Acids Research · doi:10.1093/nar/21.19.4599 · Cited by 174 · see citing works
Complete mitochondrial genome sequence of Piaractus mesopotamicus (Holmberg, 1887)
Pimentel, J. D. S. M., do Carmo, A. O., Maciel, D. D. C. L., et al. (2014) · Mitochondrial DNA Part A · doi:10.3109/19401736.2014.971297 · Cited by 7 · see citing works
Analysis of Characteristic of Codon Usage in waxy Gene of Zea mays
Yu-bi, H. (2008) · Yumi kexue · Cited by 8 · see citing works
Stop codons in bacteria are not selectively equivalent
Povolotskaya, I., Kondrashov, F. A., Ledda, A., & Vlasov, P. K. (2012) · Biology Direct · doi:10.1186/1745-6150-7-30 · Cited by 43 · see citing works

Authors: Gutman, G. A., & Hatfield, G. W.
Affiliations: University of California, Irvine (US)
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 1989-05
Volume: 86
Issue: 10
Pages: 3699-3703
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.86.10.3699
PMC: PMC287207
OpenAlex: W2063504601
Semantic Scholar: 2e078282edbdc0cc228e53846cc1e546a9101d97
Cited by: 261
References: 38
Citations by year: 2026: 4 · 2025: 1 · 2024: 6 · 2023: 6 · 2022: 9 · 2021: 16 · 2020: 14 · 2019: 16 · 2018: 8 · 2017: 17 · 2016: 11 · 2015: 14 · 2014: 11 · 2013: 7 · 2012: 12
FWCI: 2.73
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed (publishedVersion)
PubMed Central (submittedVersion)
Funders: University of Southern California
U.S. Public Health Service
University of California, San Diego
National Institute of General Medical Sciences (GM24330)
National Institute of Allergy and Infectious Diseases (AI-21366)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
Keywords: codon pair bias, Escherichia coli, gene expression levels, translation efficiency, protein-coding sequences, codon usage
MeSH terms: Bacterial Proteins, Codon, DNA, Bacterial, Escherichia coli, Gene Expression Regulation, Genes, Bacterial, Peptide Chain Termination, Translational, Probability, RNA, Messenger

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Nonrandom utilization of codon pairs in Escherichia coli.

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